Project summary We have known for over a century that germline variants in outbred mice strongly influence cancer susceptibility. This observation is consistent with decades of clinical experience with sporadic cancers in which a family history of a specific form of cancer is often most predictive of an individual's cancer risk. For instance, acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, but the overall risk and subtype distribution of ALL is strongly influenced by genetic variation associated with racial differences. Understanding the contribution of germline variation to ALL susceptibility is an important area of research in order to address persistent racial disparities in ALL outcomes. We previously characterized a novel mouse model of T-cell acute lymphoblastic leukemia (T-ALL) that is driven by Sleeping Beauty (SB) transposon mutagenesis. Recently we discovered that at least two recessive loci in the C57BL/6N sub-strain confer susceptibility to SB-induced T-ALL. Our long-term goal is to identify mechanisms by which germline variation in humans influences the initiation and progression of specific forms of ALL through the study of engineered mouse models. The objectives of the current proposal is to better define the nature of the genetic contribution of sub-strain in our leukemia models and to identify specific candidate genes that are responsible for the phenotypic variation. The rationale for this proposal is that the identification of genes and pathways that mediate T-ALL risk in our models will provide novel candidates to pursue in studying inherited T-ALL risk in humans. The focus of Specific Aim 1 is to more finely map the recessive risk alleles and to provide a comprehensive sequences analysis (both genomic and transcriptomic) of the risk loci we have identified. Specific Aim 2 will begin to characterize the biological mechanism(s) by which these alleles contribute to disease risk. This will be done by generating bone marrow chimeric mice to determine if the risk alleles act directly through the tumor cell of origin (e.g. hematopoietic cells) or through stromal cell types. If successful, the identification of genes and pathways that mediate T-ALL risk in our models will provide novel candidates to pursue in studying inherited T-ALL risk in humans.